Disseminated intravascular coagulation (DIC), which is closely related to platelet activation, is a key factor leading to high mortality in sepsis. The release of contents from plasma membrane rupture after platelet death further aggravates thrombosis. Nerve injury-induced protein 1 (NINJ1) is a cell membrane protein that mediates membrane disruption, a typical marker of cell death, through oligomerization. Nevertheless, whether NINJ1 is expressed in platelets and regulates the platelet function remains unclear. The aim of this study was to evaluate the expression of NINJ1 in human and murine platelets and elucidate the role of NINJ1 in platelets and septic DIC. In this study, NINJ1 blocking peptide (NINJ126-37) was used to verify the effect of NINJ1 on platelets in vitro and in vivo. Platelet αIIbβ3 and P-selectin were detected by flow cytometry. Platelet aggregation was measured by turbidimetry. Platelet adhesion, spreading and NINJ1 oligomerization were examined by immunofluorescence. Cecal perforation-induced sepsis and FeCl3-induced thrombosis models were used to evaluate the role of NINJ1 in platelet, thrombus and DIC in vivo. We found that inhibition of NINJ1 alleviates platelet activation in vitro. The oligomerization of NINJ1 is verified in membrane-broken platelets, which is regulated by the PANoptosis pathway. In vivo studies demonstrate that inhibition of NINJ1 effectively reduces platelet activation and membrane disruption, thus suppressing platelet-cascade reaction and leading to anti-thrombosis and anti-DIC in sepsis. These data demonstrate that NINJ1 is critical in platelet activation and plasma membrane disruption, and inhibition of NINJ1 effectively reduces platelet-dependent thrombosis and DIC in sepsis. This is the first study to reveal the key role of NINJ1 in platelet and its related disorders.